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Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study.
Wada, T, Inagaki, M, Yoshinari, T, Terata, R, Totsuka, N, Gotou, M, Hashimoto, G
Clinical and experimental nephrology. 2021;(2):120-130
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Abstract
BACKGROUND We investigated the efficacy and safety of apararenone (MT-3995), a non-steroidal compound with mineralocorticoid receptor agonist activity, in patients with stage 2 diabetic nephropathy (DN). METHODS The study had two parts: a dose-response, parallel-group, randomized, double-blind, placebo-controlled, multicenter, phase 2, 24-week study and an open-label, uncontrolled, 28-week extension study. Primary and secondary endpoints were the 24-week percent change from baseline in urine albumin to creatine ratio (UACR) and 24- and 52-week UACR remission rates. Safety parameters were changes from baseline in estimated glomerular filtration rate (eGFR) and serum potassium at 24 and 52 weeks, and incidences of adverse events (AEs) and adverse drug reactions (ADRs). RESULTS In the dose-response period, 73 patients received placebo and 73, 74, and 73 received apararenone 2.5 mg, 5 mg, and 10 mg, respectively. As a percentage of baseline, mean UACR decreased to 62.9%, 50.8%, and 46.5% in the 2.5 mg, 5 mg, and 10 mg apararenone groups, respectively, at week 24 (placebo: 113.7% at week 24; all P < 0.001 vs placebo). UACR remission rates at week 24 were 0.0%, 7.8%, 29.0%, and 28.1% in the placebo and apararenone 2.5 mg, 5 mg, and 10 mg groups, respectively. eGFR tended to decrease and serum potassium tended to increase, but these events were not clinically significant. AE incidence increased with dose while ADR incidence did not. CONCLUSION The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable. CLINICAL TRIAL REGISTRATION NCT02517320 (dose-response study) and NCT02676401 (extension study).
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Spironolactone Use and Improved Outcomes in Patients With Heart Failure With Preserved Ejection Fraction With Resistant Hypertension.
Tsujimoto, T, Kajio, H
Journal of the American Heart Association. 2020;(23):e018827
Abstract
Background Resistant hypertension is a salt-retaining condition possibly attributable to inappropriate aldosterone secretion. Methods and Results This study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Patients with heart failure with preserved ejection fraction (HFpEF) with (n=1004) and without (n=2437) resistant hypertension were included. Resistant hypertension was defined as systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg in a patient with hypertension, despite the concurrent use of a renin-angiotensin system blocker (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker), a calcium channel blocker, and a diuretic; or as those patients using ≥4 classes of antihypertensive medication. The primary outcome was a composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization. We analyzed hazard ratios (HRs) for outcomes with 95% CIs in the spironolactone group and compared them with the placebo group using Cox proportional hazard models. The risk of primary outcome events in patients with HFpEF with resistant hypertension was significantly lower in the spironolactone group than in the placebo group (HR, 0.70; 95% CI, 0.53-0.91; P=0.009), whereas the risk of primary outcome events in patients with HFpEF without resistant hypertension was not significantly different between the 2 groups (HR, 1.00; 95% CI, 0.83-1.20; P=0.97). There was a significant interaction between spironolactone use and resistant hypertension (P=0.03). Similar associations were also observed in patients with HFpEF from the Americas (United States, Canada, Brazil, and Argentina) only. Conclusions Spironolactone may be an effective add-on medication for patients with HFpEF with resistant hypertension taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers, and diuretics.
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Higher doses of loop diuretics limit uptitration of angiotensin-converting enzyme inhibitors in patients with heart failure and reduced ejection fraction.
Ter Maaten, JM, Martens, P, Damman, K, Dickstein, K, Ponikowski, P, Lang, CC, Ng, LL, Anker, SD, Samani, NJ, Filippatos, G, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2020;(8):1048-1059
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Abstract
BACKGROUND Loop diuretics are frequently prescribed to patients with heart failure and reduced ejection fraction (HFrEF) for the treatment of congestion; however, they might hamper uptitration of inhibitors of the renin-angiotensin system. METHODS Loop diuretic dose at baseline was recorded in 2338 patients with HFrEF enrolled in BIOSTAT-CHF, an international study of HF patients on loop diuretic therapy who were eligible for uptitration of angiotensin-converting enzyme inhibitors (ACEi)/mineralocorticoid receptor antagonists (MRA). The association between loop diuretic dose and uptitration of ACEi/MRA to percentage of target dose was adjusted for a previously published model for likelihood of uptitration and a propensity score. RESULTS Baseline median loop diuretic dose was 40 [40-100] mg of furosemide or equivalent. Higher doses of loop diuretics were associated with higher NYHA class and higher levels of NT-proBNP, more severe signs and symptoms of congestion, more frequent MRA use, and lower doses of ACEi reached at 3 and 9 months (all P < 0.01). After propensity adjustment, higher doses of loop diuretics remained significantly associated with poorer uptitration of ACEi (Beta per log doubling of loop diuretic dose: - 1.66, P = 0.021), but not with uptitration of MRAs (P = 0.758). Higher doses of loop diuretics were independently associated with an increased risk of all-cause mortality or HF hospitalization [HR per doubling of loop diuretic dose: 1.06 (1.01-1.12), P = 0.021]. CONCLUSIONS Higher doses of loop diuretics limited uptitration of ACEi in patients with HFrEF and were associated with a higher risk of death and/or HF hospitalization, independent of their lower likelihood of uptitration and higher baseline risk. This figure was created with images adapted from Servier Medical Art licensed under a Creative Commons Attribution 3.0.
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Association Between Acute Fall in Estimated Glomerular Filtration Rate After Treatment for Primary Aldosteronism and Long-Term Decline in Renal Function.
Kobayashi, H, Abe, M, Nakamura, Y, Takahashi, K, Fujita, M, Takeda, Y, Yoneda, T, Kurihara, I, Itoh, H, Tsuiki, M, et al
Hypertension (Dallas, Tex. : 1979). 2019;(3):630-638
Abstract
Primary aldosteronism causes renal structural damage after glomerular hyperfiltration, and primary aldosteronism-specific treatment leads to an acute fall in estimated glomerular filtration rate (eGFR). We investigated whether this change affected the long-term eGFR slope in a retrospective cohort from the multicenter Japan Primary Aldosteronism Study. We allocated patients with primary aldosteronism to the adrenalectomy (n=202) and MR (mineralocorticoid receptor) antagonist (n=303) groups based on their treatment history and analyzed the association between the initial eGFR fall and long-term eGFR slope. The increased age, low serum potassium levels, high eGFR, and high plasma aldosterone levels were independent predictors for a large initial eGFR fall in both groups. Our analysis of tertiles based on the initial eGFR fall revealed that in the MR antagonist group, patients with a small initial eGFR fall had a significantly steeper long-term eGFR slope than those with a large initial fall (tertile 1 versus 2, P=0.025; tertile 1 versus 3, P=0.017). These associations were not identified in the adrenalectomy group. Thus, the smaller the acute fall in eGFR by initiation of MR antagonists, the greater was the rate of long-term eGFR decline. While the acute fall in eGFR induced by primary aldosteronism-specific treatment is occasionally a clinical concern, our findings highlight the favorable implications of the acute fall with respect to long-term renal outcomes.
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Clinical and biochemical outcomes after adrenalectomy and medical treatment in patients with unilateral primary aldosteronism.
Katabami, T, Fukuda, H, Tsukiyama, H, Tanaka, Y, Takeda, Y, Kurihara, I, Ito, H, Tsuiki, M, Ichijo, T, Wada, N, et al
Journal of hypertension. 2019;(7):1513-1520
Abstract
OBJECTIVES Current clinical guidelines of primary aldosteronism recommend adrenalectomy (AdX) for unilateral primary aldosteronism based on the studies showing the potential superiority of AdX over the medical treatment. However, since most medically treated cases consisted of bilateral primary aldosteronism and all surgically treated cases consisted of unilateral primary aldosteronism, the different subtype of primary aldosteronism could be a bias for their effects. This study compared the effects of AdX and medical therapy in patients with unilateral primary aldosteronism confirmed by adrenal vein sampling. METHODS Of the 339 patients with unilateral primary aldosteronism in the Japan Primary Pldosteronism Study data base, unilateral AdX and treatment with mineral corticoid receptor antagonists (MRAs) was done in 276 patients (AdX group) and in 63 patients (MRAs group), respectively. The effects were compared by the clinical (improvement of blood pressure) and biochemical outcomes (improvement of hypokalemia). RESULTS At baseline, use of potassium replacement, plasma aldosterone concentration, aldosterone-to-renin ratio, estimated glomerular filtration rate, and prevalence of adrenal mass on imaging were higher in the AdX group than in the MRAs group. At 6 months after commencement of specific treatment for primary aldosteronism, clinical outcome and biochemical outcome in the AdX group were superior than those in the MRAs group. The difference of the outcome between the two groups were the case even after adjusting for the different clinical backgrounds in the two groups before the specific treatment. CONCLUSION Our study provides evidence that AdX is the first choice of treatment in the patients with unilateral primary aldosteronism in terms of clinical and biochemical outcome.
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Canrenone on cardiovascular mortality in congestive heart failure: CanrenOne eFFects on cardiovascular mortality in patiEnts with congEstIve hearT failure: The COFFEE-IT study.
Derosa, G, Maffioli, P, Scelsi, L, Bestetti, A, Vanasia, M, Cicero, AFG, Spinardi, L, Bentivenga, C, Esposti, DD, Caprio, M, et al
Pharmacological research. 2019;:46-52
Abstract
AIM: To evaluate canrenone effects compared to other therapies on cardiovascular mortality in patients with chronic heart failure (CHF) and preserved systolic function after 10 years of evaluation. METHODS We enrolled 532 patients with CHF and preserved systolic function. Patients were followed with a mean follow-up of 10 years: 166 patients were in therapy with canrenone, while 336 patients were in conventional therapy. We re-evaluated these data after 10 years, together with the rate of death and survival. RESULTS Systolic and diastolic blood pressure were lower with canrenone compared to the group not treated with canrenone, both in supine and orthostatism. In the group treated with canrenone we recorded a lower value of fasting plasma glucose and glycated hemoglobin. Uric acid was lower in the group treated with canrenone, no differences were observed regarding creatinine, sodium, potassium, brain natriuretic peptide (BNP), pro-BNP or plasma renin activity (PRA), while aldosterone levels were reduced in canrenone group compared to control. After 10 years, left ventricular mass was lower in canrenone group. We recorded a more pronounced progression of NYHA class in controls compared to patients treated with canrenone, with also a higher number of deaths. A higher number of deaths was recorded in control group in the 68-83 years range compared to canrenone. A higher incidence of death was reported among patients without hypercholesterolemia in control group; this was not significant in patients treated with canrenone. A longer survival was observed in patients treated with canrenone. CONCLUSION Administered to patients with CHF and preserved systolic fraction, reduced mortality and extended the life.
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Mineralocorticoid receptor antagonist pre-treatment and early post-treatment to minimize reperfusion injury after ST-elevation myocardial infarction: The MINIMIZE STEMI trial.
Bulluck, H, Fröhlich, GM, Nicholas, JM, Mohdnazri, S, Gamma, R, Davies, J, Sirker, A, Mathur, A, Blackman, D, Garg, P, et al
American heart journal. 2019;:60-67
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Abstract
BACKGROUND Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients. METHODS STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months. RESULTS Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, P = .574). There was also no difference in acute MI size (26 ± 16% versus 23 ± 14%, P = .425) or myocardial salvage (26 ± 12% versus 24 ± 8%, P = .456). At follow-up, there was a trend towards an improvement in LVEF (placebo: 49 ± 8%, MRA: 54 ± 11%, P = .053), and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: -12.2 (95% CI -20.3 to -4.4)%, P = .003) and LVESV (mean difference: -18.2 (95% CI -30.1 to -6.3)%, P = .003). CONCLUSION This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings.